chr8-1857879-G-GATCTATCTATCTATCT

Variant names:

• chr8-1857879-G-GATCTATCTATCTATCT
• rs35698984
• NM_014629.4:c.38-48_38-33dupATCTATCTATCTATCT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014629.4(ARHGEF10):​c.38-48_38-33dupATCTATCTATCTATCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 113,704 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 1 publications found

Genes affected

ARHGEF10 (HGNC:14103): (Rho guanine nucleotide exchange factor 10) This gene encodes a Rho guanine nucleotide exchange factor (GEF). Rho GEFs regulate the activity of small Rho GTPases by stimulating the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and may play a role in neural morphogenesis. Mutations in this gene are associated with slowed nerve conduction velocity (SNCV). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ARHGEF10 Gene-Disease associations (from GenCC):

• autosomal dominant slowed nerve conduction velocity

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• hereditary peripheral neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• peripheral neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KBTBD11-OT1 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 25 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	NM_014629.4	MANE Select	c.38-48_38-33dupATCTATCTATCTATCT		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-48_38-33dupATCTATCTATCTATCT		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-48_38-33dupATCTATCTATCTATCT		intron	N/A	NP_001295082.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.38-81_38-80insATCTATCTATCTATCT		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-81_110-80insATCTATCTATCTATCT		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-81_38-80insATCTATCTATCTATCT		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.000220 AC: 25 AN: 113632 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000371

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.000276

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000146

Gnomad OTH AF: 0.000644

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000196 AC: 94 AN: 480664 Hom.: 0 AF XY: 0.000176 AC XY: 45 AN XY: 255064

African (AFR) AF: 0.00 AC: 0 AN: 11426

American (AMR) AF: 0.0000438 AC: 1 AN: 22832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13808

East Asian (EAS) AF: 0.00123 AC: 34 AN: 27588

South Asian (SAS) AF: 0.000329 AC: 15 AN: 45536

European-Finnish (FIN) AF: 0.0000292 AC: 1 AN: 34240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2300

European-Non Finnish (NFE) AF: 0.000131 AC: 39 AN: 297946

Other (OTH) AF: 0.000160 AC: 4 AN: 24988

GnomAD4 genome AF: 0.000220 AC: 25 AN: 113704 Hom.: 0 Cov.: 24 AF XY: 0.000163 AC XY: 9 AN XY: 55142

African (AFR) AF: 0.000294 AC: 8 AN: 27228

American (AMR) AF: 0.00 AC: 0 AN: 11318

Ashkenazi Jewish (ASJ) AF: 0.000371 AC: 1 AN: 2696

East Asian (EAS) AF: 0.00139 AC: 6 AN: 4316

South Asian (SAS) AF: 0.000275 AC: 1 AN: 3630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.000146 AC: 8 AN: 54642

Other (OTH) AF: 0.000639 AC: 1 AN: 1564

Alfa AF: 0.00 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35698984; hg19: chr8-1806045;